CaltechAUTHORS
Published October 12, 2022 | Version Submitted + Supplemental Material
Discussion Paper Open

Structure of the Inmazeb cocktail and resistance to escape against Ebola virus

Creators

  • 1. ROR icon La Jolla Institute For Allergy & Immunology
  • 2. ROR icon Boston University
  • 3. ROR icon Regeneron (United States)
  • 4. ROR icon California Institute of Technology
  • 5. ROR icon Arizona State University
  • 6. ROR icon Environmental Molecular Sciences Laboratory
  • 7. ROR icon Pacific Northwest National Laboratory
  • 8. ROR icon Washington University in St. Louis
  • 9. ROR icon University of California, San Francisco

Abstract

Monoclonal antibodies can provide important pre- or post-exposure protection against disease for those not yet vaccinated or in individuals that fail to mount a protective immune response after vaccination. A key concern in use of monotherapy monoclonal antibody products lies in the high risk of mutagenic escape. Inmazeb (REGN-EB3), a three-antibody cocktail against Ebola virus, demonstrated efficacy in lessening disease course and improving survival in a randomized, controlled trial. Here we present the cryoEM structure at 3.1 Å of the Ebola virus glycoprotein, determined without symmetry averaging, in a simultaneous complex with eight Fab fragments of antibodies in the Inmazeb cocktail. This structure allows modeling of previously disordered portions of the glycan cap, maps the non-overlapping epitopes of Inmazeb, and illuminates the basis for complementary activities, as well as residues that are critical for resistance to escape by each component of this cocktail and other clinically relevant antibodies. We also provide direct evidence that, unlike monotherapy treatments, including those targeting conserved epitopes, the Inmazeb protects against the rapid emergence of EBOV escape mutants and supports the benefit of the combination approach.

Additional Information

The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. We gratefully acknowledge our funding from NIAID U19 AI142790, Consortium for Immunotherapeutics against Emerging Viral Threats (E.O.S, C.W.D.) and U.S. Department of Health and Health Services Contract No. HHSO100201700016C (Regeneron). A portion of this project has been funded in part with federal funds from the Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority, under OT number HHSO100201700020C. We thank all the staff of the NIH who supported this study, in particular Kaleb Sharer, Russel Byrum, Jennifer Jackson, Sarah Klim, Danny Ragland, Marisa St Claire and Lisa Hensley. The authors would like to thank Kristen Tramaglini for continuous support with this project. Author Contributions: Conceptualization, E.O.S, C.A.K, A.B. Methodology, V.R, B.F, A.R, H.C, A.P, K.P, R.C, R.D Investigation, V.R, H.C, C.H, B.F, A.B, A.R, E.A, K.S, S.H, D.P, E.W, S.G, R.C, K.P, R.D, R.M.B, C.D Formal analysis, V.R, C.H, B.F, A.B, A.R, M.F, R.D, K.P Writing ± original draft, V.R, E.O.S., B.F., A.B. Writing ± review & editing, V.R, E.O.S, B.F, M.F, S.S, A.P, C.A.K, A.B Visualization, V.R, B.F., A.R., H.C. Supervision, E.O.S, C.A.K, M.F., A.B. Resources, E.O.S, D.W, C.A.K, A.B, A.R,. Funding Acquisition, E.O.S, C.A.K. Competing Interest Statement. Regeneron authors own options and/or stock of the company. C.A.K. is an officer of Regeneron

Attached Files

Submitted - 2022.10.11.511805v1.full.pdf

Supplemental Material - media-1.pdf

Supplemental Material - media-2.pdf

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2022.10.11.511805v1.full.pdf

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Additional details

Identifiers

Eprint ID
120312
Resolver ID
CaltechAUTHORS:20230322-101630000.19

Related works

Describes
https://resolver.caltech.edu/CaltechAUTHORS:20230322-76136000.1 (URL)

Funding

NIH
U19 AI142790
Department of Health and Human Services
HHSO100201700016C
Department of Health and Human Services
HHSO100201700020C

Dates

Created
2023-03-22
Created from EPrint's datestamp field
Updated
2023-03-22
Created from EPrint's last_modified field